Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/18—One oxygen or sulfur atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to a sodium salt of JV-((i,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)-i-isopropyl-ifT-pyrazole-3-sulfonamide and to hydrates, solvates and polymorphic forms thereof.
• the present invention further relates to pharmaceutical compositions comprising this compound and the use of this compound in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.
• NLR NOD-like receptor
• NLRP3 pyrin domain-containing protein 3
• NLRP3 is an intracellular signalling molecule that senses many pathogen-derived, environmental and host-derived factors. Upon activation, NLRP3 binds to apoptosis- associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerises to form a large aggregate known as an ASC speck.
• ASC caspase activation and recruitment domain
• Polymerised ASC in turn interacts with the cysteine protease caspase-i to form a complex termed the inflammasome.
• caspase-i which cleaves the precursor forms of the proinflammatory cytokines IL-ib and IL-18 (termed pro-IL-ib and pro-IL-18 respectively) to thereby activate these cytokines.
• Caspase-i also mediates a type of inflammatory cell death known as pyroptosis.
• the ASC speck can also recruit and activate caspase-8, which can process pro-IL-ib and pro-IL-18 and trigger apoptotic cell death.
• Caspase-i cleaves pro-IL-ib and pro-IL-18 to their active forms, which are secreted from the cell. Active caspase-i also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-i also mediates the release of alarmin molecules such as IL-33 and high mobility group box 1 protein (HMGBi). Caspase-i also cleaves intracellular IL-1R2 resulting in its degradation and allowing the release of IL-ia. In human cells caspase-i may also control the processing and secretion of IL-37. A number of other caspase-i substrates such as components of the cytoskeleton and glycolysis pathway may contribute to caspase-i-dependent inflammation.
• NLRP3-dependent ASC specks are released into the extracellular environment where they can activate caspase-i, induce processing of caspase-i substrates and propagate inflammation.
• cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury.
• IL-ib signalling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF.
• IL-ib and IL-18 synergise with IL-23 to induce IL-17 production by memory CD4 Thi7 cells and by gd T cells in the absence of T cell receptor engagement.
• IL-18 and IL-12 also synergise to induce IFN-g production from memory T cells and NK cells driving a Thi response.
• MFS Muckle-Wells syndrome
• NLRP3 autoinflammatory syndrome
• NOMID neonatal-onset multisystem inflammatory disease
• NLRP3 A role for NLRP3 in diseases of the central nervous system is emerging, and lung diseases have also been shown to be influenced by NLRP3. Furthermore, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using Nlrp3 / mice, but there have also been insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes mellitus (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-ib signaling, resulting in cell death and inflammation.
• T2D type 2 diabetes mellitus
• Glyburide inhibits IL-ib production at micromolar concentrations in response to the activation of NLRP3 but not NLRC4 or NLRPi.
• Other previously characterised weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy ⁇ -nitrostyrene and dimethyl sulfoxide (DMSO), although these agents have limited potency and are nonspecific.
• Current treatments for NLRP3-related diseases include biologic agents that target IL-i. These are the recombinant IL-i receptor antagonist anakinra, the neutralizing IL-ib antibody canakinumab and the soluble decoy IL-i receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologic agents have been used in clinical trials for other IL-i -associated diseases.
• diarylsulfonylurea-containing compounds have been identified as cytokine release inhibitory drugs (CRIDs) (Perregaux et al.; J. Pharmacol. Exp. Ther. 299, 187- 197, 2001).
• CRIDs are a class of diarylsulfonylurea-containing compounds that inhibit the post-translational processing of IL-ib. Post-translational processing of IL-ib is accompanied by activation of caspase-i and cell death. CRIDs arrest activated monocytes so that caspase-i remains inactive and plasma membrane latency is preserved.
• sulfonylurea-containing compounds are also disclosed as inhibitors of NLRP3 (see for example, Baldwin et al, J. Med. Chem., 59(5), 1691-1710, 2016; and WO 2016/131098 Al, WO 2017/129897 Al, WO 2017/140778 Al, WO 2017/184604 Al, WO 2017/184623 Al, WO 2017/184624 Al and WO 2018/015445 Al).
• WO 2016/131098 Al discloses W-((i, 2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-iIT- pyrazole-3-sulfonamide.
• a first aspect of the present invention provides a sodium salt of IV-(( 1, 2, 3, 5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-iTf-pyrazole-3-sulfonamide, or a hydrate or solvate thereof.
• a second aspect of the present invention provides a polymorphic form of a sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-z/-/-pyrazole-3- sulfonamide, or a hydrate or solvate thereof.
• the polymorphic form of the second aspect is a polymorph of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-iii-pyrazole-3- sulfonamide monosodium salt monohydrate. Examples of such polymorphs include the polymorph referred to herein as Form l.
• the polymorphic form of the second aspect is a polymorph of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-iii-pyrazole-3- sulfonamide monosodium salt anhydrate.
• polymorphs include the polymorph referred to herein as Form 2.
• a third aspect of the present invention provides a process for preparing a sodium salt of A (i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-ifi-pyrazole-3- sulfonamide, comprising:
• a fourth aspect of the present invention provides a pharmaceutical composition comprising a salt, hydrate or solvate of the first aspect of the invention or a
• polymorphic form of the second aspect of the invention and a pharmaceutically acceptable excipient.
• Further aspects of the present invention provide medical uses and methods of treatment or prevention of a disease, disorder or condition, most especially by NLRP3 inhibition.
• Figure 1 shows XRPD analysis of the salt of Example 2.
• Figure 2 shows TGA and DSC analysis of the salt of Example 2.
• Figure 3 shows XRPD analysis of the salt of Example 3.
• FIG. 4 shows TGA and DSC analysis of the salt of Example 3.
• the salts of the present invention provide forms of iV-((i,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-i-isopropyl-ifT-pyrazole-3-sulfonamide, and in particular sodium salts, which have certain advantages over other salts and over the free acid itself.
• a first aspect of the present invention provides a sodium salt of iV-((i,2,3,5,6,7- hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-ifT-pyrazole-3-sulfonamide, or a hydrate or solvate thereof.
• iV-((i,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-i- isopropyl- JfT-pyrazole-3-sulfonamide also referred to as the free acid
• the salts of the first aspect of the present invention encompass salts having any ratio of the conjugate base of the free acid to sodium ion, for example monosodium salts, disodium salts and hemisodium salts.
• the sodium salt of N- ((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-JfT-pyrazole-3- sulfonamide is a monosodium salt.
• the salts of the first aspect of the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate.
• Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
• alcoholic solvents e.g. methanol, ethanol or isopropanol.
• the sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-z//- pyrazole-3-sulfonamide is a monohydrate or anhydrate.
• the sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-z//- pyrazole-3-sulfonamide is a monohydrate.
• the salts, hydrates and solvates of the first aspect of the invention may be in any crystalline or amorphous form or may exist as any mixture of crystalline and amorphous forms.
• the salt, hydrate and/or solvate may have a degree of crystallinity.
• the degree of crystallinity is the weight percentage of the salt, hydrate and/or solvate of the first aspect of the invention which is in one or more ciystalline forms, expressed as a percentage of the total weight of the salt, hydrate and/or solvate.
• the salts, hydrates and solvates of the first aspect of the invention preferably have a degree of crystallinity of 50% or more (e.g. 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 99 % or more). More preferably, the salts, hydrates and solvates of the first aspect of the invention are crystalline. As used herein a salt, hydrate and/or solvate of the first aspect of the invention is typically referred to as crystalline, if it has a degree of crystallinity 90% or more (e.g. 95% or more, or 99% or more).
• the sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-i-isopropyl-z//-pyrazole-3-sulfonamide is crystalline.
• the sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)- i-isopropyl-jTf-pyrazole-3-sulfonamide is a crystalline monosodium salt of N- ((1,2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-JfT-pyr azole-3- sulfonamide monohydrate.
• a crystalline salt, hydrate and/or solvate of the first aspect of the invention may exist in one or more polymorphic forms.
• Polymorphism refers to the ability of a solid substance to exist in one or more distinct crystal structures (i.e. with one or more distinct arrangements of molecules relative to each other in the crystal lattice).
• Different polymorphs of a substance may have different physical properties such as solubility, intrinsic dissolution rate and calorimetric behaviour (e.g. melting point).
• Different polymorphs may also exhibit differences in stability (e.g. differences in stability with respect to conversion to other crystalline or amorphous forms).
• the physical properties of an active pharmaceutical ingredient may affect the drug product safety performance and efficacy. It is therefore advantageous to identify polymorphic forms of a drug substance which have pharmaceutically acceptable properties.
• a second aspect of the present invention provides a polymorphic form of a sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-z//- pyrazole-3-sulfonamide, or a hydrate or solvate thereof.
• the salts, hydrates and solvates of the first aspect of the invention and the polymorphic forms of the second aspect of the invention may contain any stable isotope including, but not limited to 12 C, 13 C, ⁇ , 2 H (D), ' ⁇ N, 'TN, l6 0, 17 0, l8 0, l9 F and 127 I, and any radioisotope including, but not limited to n C, 14 C, 3 H (T), 13 N, 13 0, l8 F, 123 1, 124 I, I ⁇ T and 131 I.
• the polymorphic form of the second aspect is a polymorph of A (i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-iIT-pyrazole-3- sulfonamide monosodium salt monohydrate.
• Examples of such polymorphs include the polymorph referred to herein as Form 1.
• the Form 1 polymorph can be characterised by techniques including X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC) and/or
• XRPD data are typically those which can be obtained using CuKa radiation at 20°C.
• the term“approximate” or“approximately” when used in connection with the position of an XRPD peak typically refers to the stated position ⁇ 0.2 0 20.
• the Form 1 polymorph typically has an XRPD spectrum comprising peaks at approximately: 4.3 °20, 8.7 °20, and 20.6 °20. More typically, the Form 1 polymorph has an XRPD spectrum comprising peaks at approximately: 4.3 °20, 7.3 °20, 8.7 °20, 16.5 °20, and 20.6 °20. Still more typically, the Form 1 polymorph has an XRPD spectrum comprising peaks at approximately: 4.3 °20, 6.7 °20, 7.3 °20, 8.7 °20, 15.8 °20, 16.5 °20, and 20.6 °20.
• the Form 1 polymorph has an XRPD spectrum comprising peaks at approximately: 4.3 °20, 6.7 °20, 7.3 °20, 8.7 °20, 9.0 °20, 15.8 °20, 16.5 °20, 18.0 °20, and 20.6 °20.
• the Form l polymorph typically has an XRPD spectrum in which the 10 most intense peaks include 5 or more (e.g.
• the Form l polymorph has an XRPD spectrum in which the 10 most intense peaks include 5 or more (e.g.
• the Form l polymorph has an XRPD spectrum in which the 10 most intense peaks include 5 or more (e.g.
• the Form 1 polymorph may have an XRPD spectrum approximately as set out in Table 1 below:
• the Form l polymorph typically has a TGA profile comprising weight loss of about 4.6% to about 5.0% (e.g. weight loss of about 4.7% to about 4.9%, or weight loss of about 4.8%) between 20°C and ioo°C.
• the Form 1 polymorph typically has a DSC profile comprising a first endotherm and a second endotherm.
• the first endotherm of the Form 1 polymorph typically has an onset at a temperature in a range from about 4i°C to about 45°C (e.g. a temperature in a range from about 42°C to about 44°C, or at a temperature of about 43°C).
• the first endotherm of the Form 1 polymorph typically has a peak at a temperature in a range from about 72°C to about 70°C (e.g. a temperature in a range from about 73°C to about 75°C, or at a temperature of about 74°C).
• the first endotherm of the Form 1 polymorph typically has an enthalpy change of about 69 J/g to about 73 J/g (e.g. about 70 J/g to about 72 J/g, or about 71 J/g).
• the second endotherm of the Form 1 polymorph typically has an onset at a temperature in a range from about 177°C to about i8i°C (e.g. a temperature in a range from about 178°C to about i8o°C, or at a temperature of about 179°C).
• the second endotherm of the Form 1 polymorph typically has a peak at a temperature in a range from about i88°C to about 192°C (e.g.
• the second endotherm of the Form 1 polymorph typically has an enthalpy change of about 13 J/g to about 17 J/g (e.g. about 14 J/g to about 16 J/g, or about 15 J/g).
• the Form 1 polymorph can be obtained by a process comprising:
• the solvent mixture used in step (a) comprises water and a polar aprotic organic solvent.
• the polar aprotic organic solvent is acetone.
• the volume ratio of water to polar aprotic organic solvent is typically from 1:35 to 1:1 (e.g. from 1:20 to 1:1, or from 1:15 to 1:4, or from 1:13 to 1:6, or from 1:11 to 1:8, or about 1:9).
• iV-((i,2,3,5,6,7-hexahydro-s-indacen- 4-yl)carbamoyl)-i-isopropyl-z/J-pyrazole-3-sulfonamide free acid is treated with a solvent mixture of water and a polar aprotic organic solvent, followed by addition of a source of sodium ions to form a solution.
• the crystalline monosodium salt of N- ((1,2, 3,5,6, 7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-JfT-pyr azole-3- sulfonamide monohydrate Form 1 polymorph may be obtained from the solution by addition of a suitable antisolvent, or by a combination of addition of a suitable antisolvent and addition of seed crystals.
• Preferred antisolvents are diethyl ether, diisopropyl ether and tert-butyl methyl ether. Particularly preferred is tert-butyl methyl ether.
• the polymorphic form of the second aspect is a polymorph of w iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-iii-pyrazole-3- sulfonamide monosodium salt anhydrate.
• polymorphs include the polymorph referred to herein as Form 2.
• the Form 2 polymorph typically has an XRPD spectrum comprising peaks at
• Form 2 polymorph has an XRPD spectrum comprising peaks at approximately: 5.1 °20, 17.9 °20, 18.7 °20,
• the Form 2 polymorph has an XRPD spectrum comprising peaks at approximately: 5.1 °20, 17.1 °20, 17.9 °20, 18.7 °20, 20.1 °20, 21.7 °20, and 22.7 °20. Still further typically, the Form 2 polymorph has an XRPD 0 spectrum comprising peaks at approximately: 5.1 °20, 8.9 °20, 17.1 °20, 17.9 °20, 18.7 °20, 20.1 °20, 2O.6°20, 21.7 °20, and 22.7 °20.
• the Form 2 polymorph typically has an XRPD spectrum in which the 10 most intense peaks include 5 or more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks 25 which have an approximate 20 value selected from: 5.1 °20, 6.6 °20, 7.7 °20, 8.9 °20,
• the Form 2 polymorph has an XRPD spectrum in which the 10 most intense peaks include 5 or more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks which have an approximate 20 value selected from: 5.1 °20, 6.6 °20, 8.9 0 °20, 10.3 °20, 16.2 °20, 17.1 °20, 17.9 °20, 18.7 °20, 20.1 °20, 20.6 °20, 21-7 °20, and 22-7
• the Form 2 polymorph has an XRPD spectrum in which the 10 most intense peaks include 5 or more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks which have an approximate 20 value selected from: 5.1 °20, 8.9 °20, 16.2 °20, I7.I °20, I7.9 °20, 18.7 °20, 20.1 °20, 2O.6°20, 21-7 °20, and 22-7 °20.
• the 10 most intense peaks include 5 or more (e.g. 6 or more, 7 or more, 8 or more, 9 or more, or 10) peaks which have an approximate 20 value selected from: 5.1 °20, 8.9 °20, 16.2 °20, I7.I °20, I7.9 °20, 18.7 °20, 20.1 °20, 2O.6°20, 21-7 °20, and 22-7 °20.
• the Form 2 polymorph may have an XRPD spectrum approximately as set out in Table 2 below:
• the Form 2 polymorph typically has a TGA profile comprising weight loss of about
• the Form 2 polymorph typically has a DSC profile comprising a first endotherm, a w second endotherm and a third endotherm.
• the polymorph typically has an onset at a temperature in a range from about 6i°C to about 05°C (e.g. a temperature in a range from about 62°C to about 64°C, or at a temperature of about 03°C).
• the first endotherm of the Form 2 polymorph typically has a peak at a temperature in a range from about 73°C to about 77°C (e.g. a temperature in a range 15 from about 74°C to about 70°C, or at a temperature of about 75°C).
• the first endotherm of the Form 2 polymorph typically has an enthalpy change of about l J/g to about 5 J/g (e.g. about 2 J/g to about 4 J/g, or about 3 J/g).
• the second endotherm of the Form 2 polymorph typically has an onset at a temperature in a range from about 93°C to about 97°C (e.g. a temperature in a range from about 94°C to about 96°C, or at a temperature of about 95°C).
• the second endotherm of the Form 2 polymorph typically has a peak at a temperature in a range from about 99°C to about 103°C (e.g. a temperature in a range from about ioo°C to about 102°C, or at a temperature of about ioi°C).
• the second endotherm of the Form 2 polymorph typically has an enthalpy change of about 0.5 J/g to about 4 J/g (e.g.
• the third endotherm of the Form 2 polymorph typically has an onset at a temperature in a range from about i8o°C to about I84°C (e.g. a temperature in a range from about i8i°C to about I83°C, or at a temperature of about I82°C).
• the third endotherm of the Form 2 polymorph typically has a peak at a temperature in a range from about 196°C to about 200°C (e.g. a temperature in a range from about 197°C to about 199°C, or at a temperature of about 198°C).
• the third endotherm of the Form 2 polymorph typically has an enthalpy change of about 25 J/g to about 29 J/g (e.g. about 26 J/g to about 28 J/g, or about 27 J/g).
• the Form 2 polymorph can be obtained by a process comprising:
• step (a) IV-((i,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-i-isopropyl-z/J-pyrazole-3-siilfonamide monosodium salt is dissolved in a solvent mixture comprising water and a polar protic organic solvent to form a solution.
• the polar protic organic solvent used in step (a) is isopropyl alcohol.
• the volume ratio of water to polar protic organic solvent is typically from 1:35 to 1:1 (e.g. from 1:20 to 1:1, or from 1:15 to 1:4, or from 1:13 to 1:6, or from 1:11 to 1:8, or about 1:10).
• Further preferred processes for obtaining the Form 2 polymorph include those in which the polar protic organic solvent, source of sodium ions, means of obtaining the solid sodium salt and other features of the process are as described herein with respect to the process of the third aspect of the present invention.
• a third aspect of the present invention provides a process for preparing a salt, hydrate or solvate of the first aspect of the invention or a polymorphic form of the second aspect of the invention, the process comprising:
• the one or more polar solvents used in step (a) are a mixture of polar solvents, e.g. a mixture of water and a polar organic solvent. In such
• the volume ratio of water to polar organic solvent is typically from 1:35 to 1:1 (e.g. from 1:20 to 1:1, or from 1:15 to 1:4, or from 1:13 to 1:6, or from 1:11 to 1:8, or about 1:10, or about 1:9).
• the mixture of polar solvents may be, for example, a mixture of water and a polar protic organic solvent, or a mixture of water and a polar aprotic organic solvent.
• Suitable polar protic organic solvents include acids such as formic acid and acetic acid, and alcohols such as methanol, ethanol, isopropyl alcohol and n-butanol.
• a preferred 25 polar protic organic solvent is isopropyl alcohol.
• Suitable polar aprotic organic solvents include iV-m ethyl pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, methyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide and propylene carbonate.
• a preferred polar aprotic organic solvent is acetone. 0
• the mixture of polar solvents may be a mixture of water and isopropyl alcohol.
• the mixture of polar solvents may be a mixture of water and acetone.
• the source of sodium ions is typically a sodium salt.
• the sodium 35 salt is a solid sodium salt.
• the sodium salt is a solution of a
• sodium-ion containing compound Suitable solid sodium salts include NaCl, NaOH, Na 2 C0 3 and NaHC0 3 .
• Suitable solutions of sodium-ion containing compounds include sodium methoxide (NaOMe), sodium ethoxide (NaOEt) and sodium tert-butoxide (NaO f Bu) all in ethanol, tetrahydrofuran, or acetone or a mixture of any of these solvents with water.
• Other suitable solutions of sodium-ion containing compounds include NaCl, NaOH, Na 2 C0 3 and NaHC0 3 in water.
• a preferred source of sodium ions is sodium ethoxide (NaOEt) in ethanol or NaOH in water.
• a more preferred source of sodium ions is sodium ethoxide (NaOEt) in ethanol.
• step (a) the reaction mixture formed is a solution.
• step (a) iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i- isopropyl-Jfi-pyrazole-3-sulfonamide free acid is treated with a polar solvent or a mixture of polar solvents, followed by addition of a source of sodium ions to form a solution.
• step (a) is carried out at a temperature in the range of 5°C to ioo°C, or a range of io°C to 6o°C, or a range of 15°C to 30°C.
• the solid sodium salt of iV-((i,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl)-i-isopropyl-Jfi-pyrazole-3-sulfonamide may be obtained from the reaction mixture by evaporation of the solvent or mixture of solvents.
• the solid sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-i-isopropyl-Jhf-pyrazole-3-sulfonamide may be obtained from the reaction mixture by addition of a suitable antisolvent.
• the volume ratio of solvent or mixture of solvents to antisolvent is typically from 1:1 to 1:10 (e.g. from 1:1.5 to 1:8, or from 1:2 to 1:6, or about 1:3, or about 1:5).
• the solid sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl)-i-isopropyl-z//-pyrazole-3-sulfonamide may be obtained from the reaction mixture by addition of seed crystals.
• the solid sodium salt of iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-z/-/-pyrazole- 3-sulfonamide may be obtained from the reaction mixture by a combination of addition of a suitable antisolvent and addition of seed crystals.
• Suitable antisolvents include non-polar solvents such as hexane, heptane, cyclohexane, toluene, benzene, 1,4-dioxane, chloroform, dichloromethane, diethyl ether, diisopropyl ether and tert-butyl methyl ether. Diethyl ether, diisopropyl ether and tert-butyl methyl ether are preferred. Particularly preferred is tert-butyl methyl ether.
• step (b) is carried out at a temperature in the range of 5°C to ioo°C, or a range of io°C to 6o°C, or a range of 15°C to 30°C.
• a fourth aspect of the present invention provides a pharmaceutical composition comprising a salt, hydrate or solvate of the first aspect of the invention or a
• sugars conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids
• the pharmaceutical composition of the fourth aspect of the invention additionally comprises one or more further active agents.
• the pharmaceutical composition of the fourth aspect of the invention may be provided as a part of a kit of parts, wherein the kit of parts comprises the pharmaceutical composition of the fourth aspect of the invention and one or more further pharmaceutical compositions, wherein the one or more further pharmaceutical compositions each comprise a pharmaceutically acceptable excipient and one or more further active agents.
• a fifth aspect of the invention provides a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a
• composition of the fourth aspect of the invention for use in medicine, and/ or for use in the treatment or prevention of a disease, disorder or condition.
• the use comprises the administration of the salt, hydrate, solvate,
• the use comprises the co-administration of one or more further active agents.
• treatment refers equally to curative therapy, and
• beneficial or desired physiological results include, but are not limited to, the alleviation of symptoms, the prevention of symptoms, the diminishment of extent of disease, the stabilisation (i.e., not worsening) of a condition, the delay or slowing of progression/worsening of a condition/symptoms, the amelioration or palliation of the condition/symptoms, and remission (whether partial or total), whether detectable or undetectable.
• composition of the present invention relates to prophylactic or preventative therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition.
• prevention includes both the avoidance of occurrence of the disease, disorder or condition, and the delay in onset of the disease, disorder or condition. Any statistically significant (p ⁇ 0.05) avoidance of occurrence, delay in onset or reduction in risk as measured by a controlled clinical trial may be deemed a prevention of the disease, disorder or condition.
• Subjects amenable to prevention include those at heightened risk of a disease, disorder or condition as identified by genetic or biochemical markers.
• the genetic or biochemical markers are appropriate to the disease, disorder or condition under consideration and may include for example, inflammatory biomarkers such as C-reactive protein (CRP) and monocyte chemoattractant protein 1 (MCP-i) in the case of inflammation; total cholesterol, triglycerides, insulin resistance and C-peptide in the case of NAFLD and NASH; and more generally IIhb and IL18 in the case of a disease, disorder or condition responsive to NLRP3 inhibition.
• CRP C-reactive protein
• MCP-i monocyte chemoattractant protein 1
• a sixth aspect of the invention provides the use of a salt, hydrate or solvate of the first aspect of the invention or a polymorphic form of the second aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.
• the treatment or prevention comprises the administration of the salt, hydrate, solvate, polymorphic form or medicament to a subject.
• the treatment or prevention comprises the co-administration of one or more further active agents.
• a seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition.
• the method further comprises the step of co- administering an effective amount of one or more further active agents.
• the administration is to a subject in need thereof.
• An eighth aspect of the invention provides a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the treatment or prevention of a disease, disorder or condition in an individual, wherein the individual has a germline or somatic non-silent mutation in NLRP3.
• the mutation may be, for example, a gain-of-function or other mutation resulting in increased NLRP3 activity.
• the use comprises the administration of the salt, hydrate, solvate, polymorphic form or pharmaceutical composition to the individual.
• the use comprises the co-administration of one or more further active agents.
• the use may also comprise the diagnosis of an individual having a germline or somatic non-silent mutation in NLRP3, wherein the salt, hydrate, solvate, polymorphic form or pharmaceutical composition is administered to an individual on the basis of a positive diagnosis for the mutation.
• identification of the mutation in NLRP3 in the individual may be by any suitable genetic or biochemical means.
• a ninth aspect of the invention provides the use of a salt, hydrate or solvate of the first aspect of the invention or a polymorphic form of the second aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition in an individual, wherein the individual has a germline or somatic non- silent mutation in NLRP3.
• the mutation may be, for example, a gain-of-function or other mutation resulting in increased NLRP3 activity.
• the treatment or prevention comprises the administration of the salt, hydrate, solvate, polymorphic form or medicament to the individual.
• the treatment or prevention comprises the co-administration of one or more further active agents.
• the treatment or prevention may also comprise the diagnosis of an individual having a germline or somatic non-silent mutation in NLRP3, wherein the salt, hydrate, solvate, polymorphic form or medicament is administered to an individual on the basis of a positive diagnosis for the mutation.
• identification of the mutation in NLRP3 in the individual may be by any suitable genetic or biochemical means.
• a tenth aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the steps of diagnosing of an individual having a germline or somatic non-silent mutation in NLRP3, and administering an effective amount of a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a
• the method further comprises the step of co-administering an effective amount of one or more further active agents.
• the administration is to a subject in need thereof.
• the disease, disorder or condition may be a disease, disorder or condition of the immune system, the cardiovascular system, the endocrine system, the gastrointestinal tract, the renal system, the hepatic system, the metabolic system, the respiratory system, the central nervous system, may be a cancer or other malignancy, and/or may be caused by or associated with a pathogen.
• these general embodiments defined according to broad categories of diseases, disorders and conditions are not mutually exclusive.
• any particular disease, disorder or condition may be categorized according to more than one of the above general embodiments.
• a non-limiting example is type I diabetes which is an autoimmune disease and a disease of the endocrine system.
• the disease, disorder or condition is responsive to NLRP3 inhibition.
• NLRP3 inhibition refers to the complete or partial reduction in the level of activity of NLRP3 and includes, for example, the inhibition of active NLRP3 and/ or the inhibition of activation of NLRP3.
• NLRP3 has been implicated in a number of autoinflammatory diseases, including Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet’s syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook etal, Eur. J. Immunol., 40: 595-653, 2010).
• FMF Familial Mediterranean fever
• TRAPS TNF receptor associated periodic syndrome
• HIDS hyperimmunoglobulinemia D and periodic fever syndrome
• PAPA pyogenic arthritis
• PAPA pyoderma gangrenosum and acne
• Sweet’s syndrome chronic nonbacterial osteomyelitis
• acne vulgaris Cook etal, Eur. J. Immunol., 40: 595-653, 2010.
• CAPS chronic nonbacterial osteomyelitis
• CAPS are heritable diseases characterized by recurrent fever and inflammation and are comprised of three autoinflammatory disorders that form a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle- Wells syndrome (MWS), and chronic infantile cutaneous neurological articular syndrome (CINCA; also called neonatal-onset multisystem inflammatory disease, NOMID), and all have been shown to result from gain-of-function mutations in the NLRP3 gene, which leads to increased secretion of IL-ib.
• FCAS familial cold autoinflammatory syndrome
• MWS Muckle- Wells syndrome
• CINCA chronic infantile cutaneous neurological articular syndrome
• NOMID neonatal-onset multisystem inflammatory disease
• autoimmune diseases have been shown to involve NLRP3 including, in particular, multiple sclerosis, type-i diabetes (TiD), psoriasis, rheumatoid arthritis
• NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo etal, Am. J. Pathol., 184: 42-54, 2014 and Kim et al. Am J Respir Crit Care Med. 2017 196(3): 283-97). NLRP3 has also been suggested to have a role in a number of central nervous system
• Parkinson's disease PD
• AD Alzheimer's disease
• AD Alzheimer's disease
• Huntington's disease cerebral malaria
• brain injury from pneumococcal meningitis Walsh et al, Nature Reviews, 15: 84-97, 2014, and Dempsey etal. Brain. Behav.
• NRLP3 activity has also been shown to be involved in various metabolic diseases including type 2 diabetes (T2D), atherosclerosis, obesity, gout, pseudo-gout, metabolic syndrome (Wen etal., Nature Immunology, 13: 352-357, 2012; Duewell etal, Nature, 464: 1357-1361, 2010; Strowig etal, Nature, 481: 278- 286, 2012), and non-alcoholic steatohepatitis (Mridha et al. J Hepatol. 201766(5): 1037-46).
• NLRP3 via IL-ib has also been suggested in atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart J. 201738(11): 828-36), heart failure (Sano etal. J AM. Coll. Cardiol. 2018 71(8): 875-66), aortic aneurysm and dissection (Wu etal. Arterioscler. Thromb. Vase. Biol. 201737(4): 694-706), and other cardiovascular events (Ridker etal., N Engl J Med., doi: 10.1056/ NEJMoai 707914, 2017).
• Other diseases in which NLRP3 has been shown to be involved include: ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al.,
• NLRP3 inflammasome has been found to be activated in response to oxidative stress, and UVB irradiation (Schroder et al., Science, 327: 296-300, 2010). NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 40: 366-386, 2017).
• the inflammasome, and NLRP3 specifically, has also been proposed as a target for modulation by various pathogens including viruses such as DNA viruses (Amsler et al., Future Virol. (2013) 8(4), 357-370).
• NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology 166: 1-15, 2011; and Masters Clin. Immunol. 2013).
• IL-ib has been implicated in the pathogenesis of many cancers.
• several previous studies have suggested a role for IL-ib in cancer invasiveness, growth and metastasis, and inhibition of IL-ib with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomised, double-blind, placebo-controlled trial (Ridker et al. Lancet, S0140- 6736(i7)32247-X, 2017).
• NLRP3 inflammasome Activation of the NLRP3 inflammasome has also been shown to mediate chemoresistance of tumour cells to 5-Fluorouracil (Feng et al. J Exp Clin Cancer Res. 201721; 36(1): 81), and activation of NLRP3 inflammasome in peripheral nerve contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol Pain. 2017; 13: 1-11).
• NLRP3 has also been shown to be required for the efficient control of viral, bacterial, fungal, and helminth pathogen infections (Strowig et al, Nature, 481:278-286, 2012). Accordingly, examples of diseases, disorders or conditions which may be responsive to NLRP3 inhibition and which may be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention include:
• inflammation including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity;
• an inflammatory disorder e.g. an autoinflammatory disease, inflammation occurring as a symptom of a non-inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity
• auto-immune diseases such as acute disseminated encephalitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti- synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn’s disease, type 1 diabetes (TiD), Goodpasture’s syndrome, Graves’ disease, Guillain-Barre syndrome (GBS), Hashimoto’s disease, idiopathic thrombocytopenic purpura, Kawasaki’s disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia grav
• Reiter’s syndrome Sjogren’s syndrome
• systemic sclerosis a systemic connective tissue disorder
• Takayasu’s arteritis temporal arteritis
• warm autoimmune hemolytic anemia Wegener’s granulomatosis
• alopecia universalis Behgefs disease
• Chagas’ disease dysautonomia
• endometriosis hidradenitis suppurativa (HS)
• interstitial cystitis neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, vitiligo or vulvodynia
• HS hidradenitis suppurativa
• cancer including lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, leukaemia including acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML), adrenal cancer, anal cancer, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumours, breast cancer, cervical cancer, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), chronic myelomonocytic leukaemia (CMML), colorectal cancer, endometrial cancer, oesophagus cancer, Ewing family of tumours, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumours, gastrointestinal stromal tumour (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer
• ALL acute
• influenza virus human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flaviviruses (such as Dengue virus and Zika virus), herpes viruses (such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (Modified vaccinia virus Ankara) and Myxoma virus), adenoviruses (such as Adenovirus 5), or papillomavirus), bacterial infections (e.g.
• HAV human immunodeficiency virus
• alphavirus such as Chikungunya and Ross River virus
• flaviviruses such as Dengue virus and Zika virus
• herpes viruses such as Epstein Barr Virus, cytomegalovirus, Varicella-zoster virus, and KSHV
• poxviruses such as vaccinia virus (Modified vaccinia virus Ankara) and Myxo
• Clostridium tetani Clostridium
• Yersinia pestis a pestis ), fungal infections (e.g. from Candida or Aspergillus species), protozoan infections (e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g. from schistosoma, roundworms, tapeworms or flukes) and prion infections;
• fungal infections e.g. from Candida or Aspergillus species
• protozoan infections e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes
• helminth infections e.g. from schistosoma, roundworms, tapeworms or flukes
• central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, and amyotrophic lateral sclerosis;
• metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo-gout;
• cardiovascular diseases such as hypertension, ischaemia, reperfusion injuiy including post-MI ischemic reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysms including abdominal aortic aneurysm, and pericarditis including Dressler’s syndrome;
• cardiovascular diseases such as hypertension, ischaemia, reperfusion injuiy including post-MI ischemic reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congestive heart failure and heart failure with preserved ejection fraction, embolism, aneurysms including abdominal aortic aneurysm, and pericarditis including Dressler’s syndrome;
• respiratory diseases including chronic obstructive pulmonary disorder (COPD), asthma such as allergic asthma and steroid-resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis and idiopathic pulmonary fibrosis;
• COPD chronic obstructive pulmonary disorder
• liver diseases including non-alcoholic fatty liver disease (NAFLD) and non- alcoholic steatohepatitis (NASH) including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH);
• NAFLD non-alcoholic fatty liver disease
• NASH non-alcoholic steatohepatitis
• AFLD alcoholic fatty liver disease
• ASH alcoholic steatohepatitis
• renal diseases including chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;
• ocular diseases including those of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma;
• AMD age-related macular degeneration
• dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst-causing skin diseases, and acne conglobata;
• lymphatic conditions such as lymphangitis and Castleman's disease
• the disease, disorder or condition is selected from:
• the disease, disorder or condition is selected from:
• the disease, disorder or condition is selected from:
• NASH non-alcoholic steatohepatitis
• the disease, disorder or condition is inflammation.
• inflammation examples of inflammation that may be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention include inflammatory responses occurring in connection with, or as a result of:
• a skin condition such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis, allergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythemas, or alopecia;
• a joint condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or a seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease);
• a muscular condition such as polymyositis or myasthenia gravis
• a gastrointestinal tract condition such as inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), gastric ulcer, coeliac disease, proctitis, pancreatitis, eosinopilic gastro-enteritis, mastocytosis, antiphospholipid syndrome, or a food-related allergy which may have effects remote from the gut (e.g., migraine, rhinitis or eczema);
• a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper- responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g.
• COPD chronic obstructive pulmonary disease
• asthma including bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper- responsiveness
• bronchitis including acute rhinitis, allergic rhinitis,
• hay fever, and vasomotor rhinitis sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia;
• IPF idiopathic pulmonary fibrosis
• sarcoidosis farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia
• vascular condition such as atherosclerosis, Behcet's disease, vasculitides, or allegedlyer's granulomatosis;
• an autoimmune condition such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease;
• an ocular condition such as uveitis, allergic conjunctivitis, or vernal
• a nervous condition such as multiple sclerosis or encephalomyelitis
• x an infection or infection-related condition, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis,
• AIDS Acquired Immunodeficiency Syndrome
• mycobacterium tuberculosis mycobacterium avium intracellulare, pneumocystis carinii pneumonia, orchitis/epidydimitis, legionella, Lyme disease, influenza A, epstein-barr virus, viral encephalitis/aseptic meningitis, or pelvic inflammatory disease;
• a renal condition such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, uremia, or nephritic syndrome;
• xiii a condition of, or involving, the immune system, such as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft versus host disease;
• NASH steatohepatitis
• NASH non-alcoholic fatty liver disease
• NAFLD non-alcoholic fatty liver disease
• AFLD alcoholic fatty liver disease
• ASH alcoholic steatohepatitis
• primary biliary cirrhosis NASH
• NASH non-alcoholic fatty liver disease
• NAFLD non-alcoholic fatty liver disease
• AFLD alcoholic fatty liver disease
• ASH alcoholic steatohepatitis
• primary biliary cirrhosis primary biliary cirrhosis
• the disease, disorder or condition is an autoinflammatory disease such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS),
• CAPS cryopyrin-associated periodic syndromes
• MFS Muckle-Wells syndrome
• FCAS familial cold autoinflammatory syndrome
• FMF familial Mediterranean fever
• NOMID neonatal onset multisystem inflammatory disease
• TNF Tumour Necrosis Factor
• TRAPS Tumour Necrosis Factor
• hyperimmunoglobulinemia D and periodic fever syndrome HIDS
• deficiency of interleukin l receptor antagonist DIRA
• Majeed syndrome pyogenic arthritis
• PAPA pyoderma gangrenosum and acne syndrome
• AOSD adult-onset Still's disease
• haploinsufficiency of A20 HA20
• PGA pediatric granulomatous arthritis
• PLCG2-associated antibody deficiency and immune dysregulation PLAID
• APLAID or sideroblastic anaemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD).
• diseases, disorders or conditions which may be responsive to NLRP3 inhibition and which may be treated or prevented in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention are listed above. Some of these diseases, disorders or conditions are substantially or entirely mediated by NLRP3 inflammasome activity, and NLRP3-induced IL-ib and/or IL-18. As a result, such diseases, disorders or conditions may be particularly responsive to NLRP3 inhibition and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention. Examples of such diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal onset multisystem inflammatory disease (NOMID), familial
• FMF Mediterranean fever
• PAPA pyogenic arthritis
• HIDS hyperimmunoglobulinemia D and periodic fever syndrome
• TNF Tumour Necrosis Factor
• TRAPS Tumour Necrosis Factor
• AOSD relapsing polychondritis
• Schnitzler’s syndrome Sweet’s syndrome
• Behcet’s disease anti- synthetase syndrome, deficiency of interleukin 1 receptor antagonist (DIRA), and haploinsufficiency of A20 (HA20).
• DIRA interleukin 1 receptor antagonist
• diseases, disorders or conditions mentioned above arise due to mutations in NLRP3, in particular, resulting in increased NLRP3 activity.
• diseases, disorders or conditions may be particularly responsive to NLRP3 inhibition and may be particularly suitable for treatment or prevention in accordance with the fifth, sixth, seventh, eighth, ninth or tenth aspect of the present invention.
• diseases, disorders or conditions include cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold
• An eleventh aspect of the invention provides a method of inhibiting NLRP3, the method comprising the use of a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to inhibit NLRP3.
• the method comprises the use of a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, in combination with one or more further active agents.
• the method is performed ex vivo or in vitro, for example in order to analyse the effect on cells of NLRP3 inhibition.
• the method is performed in vivo.
• the method may comprise the step of administering an effective amount of a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to thereby inhibit NLRP3.
• the method further comprises the step of co-administering an effective amount of one or more further active agents.
• the administration is to a subject in need thereof.
• the method of the eleventh aspect of the invention may be a method of inhibiting NLRP3 in a non-human animal subject, the method comprising the steps of administering the salt, hydrate, solvate, polymorphic form or pharmaceutical composition to the non-human animal subject and optionally subsequently mutilating or sacrificing the non-human animal subject.
• a method further comprises the step of analysing one or more tissue or fluid samples from the optionally mutilated or sacrificed non-human animal subject.
• the method further comprises the step of co-administering an effective amount of one or more further active agents.
• a twelfth aspect of the invention provides a salt, hydrate or solvate of the first aspect of the invention, a polymorphic form of the second aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in the inhibition of NLRP3.
• the use comprises the administration of the salt, hydrate, solvate, polymorphic form or pharmaceutical composition to a subject.
• the salt, hydrate, solvate, polymorphic form or pharmaceutical composition is co-administered with one or more further active agents.
• a thirteenth aspect of the invention provides the use of a salt, hydrate or solvate of the first aspect of the invention or a polymorphic form of the second aspect of the invention, in the manufacture of a medicament for the inhibition of NLRP3.
• the inhibition comprises the administration of the salt, hydrate, solvate, polymorphic form or medicament to a subject.
• the salt, hydrate, solvate, polymorphic form or medicament is co-administered with one or more further active agents.
• the one or more further active agents may comprise for example one, two or three different further active agents.
• the one or more further active agents may be used or administered prior to, simultaneously with, sequentially with or subsequent to each other and/or to the salt, hydrate or solvate of the first aspect of the invention, the polymorphic form of the second aspect of the invention, or the pharmaceutical composition of the fourth aspect of the invention.
• a pharmaceutical composition of the fourth aspect of the invention may be administered wherein the pharmaceutical composition additionally comprises the one or more further active agents.
• the one or more further active agents are selected from:
• any particular active agent may be categorized according to more than one of the above general embodiments.
• a non-limiting example is urelumab which is an antibody that is an immunomodulatory agent for the treatment of cancer.
• the one or more chemotherapeutic agents are selected from abiraterone acetate, altretamine, amsacrine, anhydrovinblastine, auristatin, azathioprine, adriamycin, bexarotene, bicalutamide, BMS 184476, bleomycin, N,N- dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, cisplatin, carboplatin, carboplatin cyclophosphamide, chlorambucil, cachectin, cemadotin, cyclophosphamide, carmustine, cryptophycin, cytarabine, docetaxel, doxetaxel, doxorubicin, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine, dolastat
• heparinases heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha, interferon beta, interferon gamma, interferon inducible protein (IP- 10), interleukin-12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-i (TSP-i),
• TGF-b transforming growth factor-beta
• vasculostatin vasostatin
• vasostatin calreticulin fragment
• cytokines including interleukins, such as interleukin-2 (IL-2), or IL- 10).
• the one or more antibodies may comprise one or more monoclonal antibodies.
• the one or more antibodies are selected from abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, ceertolizumab pegol, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab
• the one or more alkylating agents may comprise an agent capable of alkylating nucleophilic functional groups under conditions present in cells, including, for example, cancer cells.
• the one or more alkylating agents are selected from cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin.
• the alkylating agent may function by impairing cell function by forming covalent bonds with amino, carboxyl, sulfhydryl, and/or phosphate groups in biologically important molecules.
• the alkylating agent may function by modifying a cell’s DNA.
• the one or more anti-metabolites may comprise an agent capable of affecting or preventing RNA or DNA synthesis.
• the one or more anti-metabolites are selected from azathioprine and/or mercaptopurine.
• the one or more anti-angiogenic agents are selected from endostatin, angiogenin inhibitors, angiostatin, angioarrestin, angiostatin (plasminogen fragment), basement-membrane collagen-derived anti- angiogenic factors (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, and/or cartilage-derived inhibitor (CD I).
• the one or more plant alkaloids and/or terpenoids may prevent microtubule function.
• the one or more plant alkaloids and/or terpenoids are selected from a vinca alkaloid, a podophyllotoxin and/or a taxane.
• the one or more vinca alkaloids may be derived from the
• the one or more taxanes are selected from taxol, paclitaxel, docetaxel and/or ortataxel.
• the one or more podophyllotoxins are selected from an etoposide and/or teniposide.
• the one or more topoisomerase inhibitors are selected from a type I topoisomerase inhibitor and/or a type II topoisomerase inhibitor, and may interfere with transcription and/or replication of DNA by interfering with DNA supercoiling.
• the one or more type I topoisomerase inhibitors may comprise a camptothecin, which may be selected from exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481.
• the one or more type II topoisomerase inhibitors may comprise an epipodophyllotoxin, which may be selected from an amsacrine, etoposid, etoposide phosphate and/or teniposide.
• the one or more mTOR (mammalian target of rapamycin, also known as the mechanistic target of rapamycin) inhibitors are selected from rapamycin, everolimus, temsirolimus and/or deforolimus.
• the one or more stilbenoids are selected from resveratrol, piceatannol, pinosylvin, pterostilbene, alpha-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin H, hemsleyanol D, hopeaphenol, trans-diptoindonesin B, astringin, piceid and/or diptoindonesin A.
• the one or more STING (Stimulator of interferon genes, also known as transmembrane protein (TMEM) 173) agonists may comprise cyclic di- nucleotides, such as cAMP, cGMP, and cGAMP, and/or modified cyclic di -nucleotides that may include one or more of the following modification features: 2'-0/3'-0 linkage, phosphorothioate linkage, adenine and/or guanine analogue, and/or 2'-0H
• the one or more cancer vaccines are selected from an HPV vaccine, a hepatitis B vaccine, Oncophage, and/or Provenge.
• the one or more immunomodulatoiy agents may comprise an immune checkpoint inhibitor.
• the immune checkpoint inhibitor may target an immune checkpoint receptor, or combination of receptors comprising, for example, CTLA-4, PD-i, PD-Li, PD-L2, T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), galectin 9, phosphatidylserine, lymphocyte activation gene 3 protein (LAG3), MHC class I, MHC class II, 4-1BB, 4-1BBL, OX40, OX40L, GITR, GITRL, CD27, CD70, TNFRSF25, TLiA, CD40, CD40L, HVEM, LIGHT, BTLA, CD160, CD80, CD244, CD48, ICOS, ICOSL, B7- H3, B7-H4, VISTA, TMIGD2, HHLA2, TMIGD2, a butyrophilin (including BTNL2), a Siglec family member, TIG
• CD86 SIRPA, CD47, VEGF, neuropilin, CD30, CD39, CD73, CXCR4, and/or CXCL12.
• the immune checkpoint inhibitor is selected from urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, CP-870893, pembrolizumab (PDi), nivolumab (PDi), atezolizumab (formerly MPDL3280A) (PD-Li), MEDI4736 (PD-Li), avelumab (PD-Li), PDR001 (PDi), BMS-986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, bavituximab, CC- 90002, bevacizumab, and/or MNRP1685A.
• the one or more antibiotics are selected from amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, ceftobi
• the one or more antibiotics may comprise one or more cytotoxic antibiotics.
• the one or more cytotoxic antibiotics are selected from an actinomycin, an anthracenedione, an anthracycline, thalidomide,
• the one or more actinomycins are selected from actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B.
• the one or more antracenediones are selected from mitoxantrone and/or pixantrone.
• the one or more anthracyclines are selected from bleomycin,
• the one or more anti-fungal agents are selected from bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoziconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravusconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine, terbina
• the one or more anti-helminthic agents are selected from benzimidazoles (including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, and flubendazole), abamectin, diethylcarbamazine, ivermectin, suramin, pyrantel pamoate, levamisole, salicylanilides (including niclosamide and oxyclozanide), and/or nitazoxanide.
• benzimidazoles including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, and flubendazole
• abamectin including albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, and flubendazole
• abamectin including albendazole, mebendazole, thiabendazole, f
• other active agents are selected from growth inhibitory agents, anti-inflammatory agents (including nonsteroidal anti-inflammatory agents), anti- psoriatic agents (including anthralin and its derivatives), vitamins and vitamin- derivatives (including retinoinds, and VDR receptor ligands), corticosteroids, ion channel blockers (including potassium channel blockers), immune system regulators (including cyclosporin, FK 506, and glucocorticoids), lutenizing hormone releasing hormone agonists (such as leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide), and/or hormones (including estrogen).
• anti-inflammatory agents including nonsteroidal anti-inflammatory agents
• anti- psoriatic agents including anthralin and its derivatives
• vitamins and vitamin- derivatives including retinoinds, and VDR receptor ligands
• corticosteroids including ion channel blockers (including potassium channel blockers)
• the subject may be any human or other animal.
• the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, sheep, goat, horse, cat, dog, rabbit, mouse etc. Most typically, the subject is a human.
• any of the medicaments employed in the present invention can be administered by oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway
• parenteral including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural
• airway including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural
• the mode of administration selected is that most appropriate to the disorder, disease or condition to be treated or prevented.
• the mode of administration may be the same as or different to the mode of administration of the salt, hydrate, solvate, polymorphic form or pharmaceutical composition of the invention.
• the salt, hydrate, solvate, polymorphic form or pharmaceutical composition of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.
• Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
• suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose.
• Corn starch and alginic acid are suitable disintegrating agents.
• Binding agents may include starch and gelatine.
• the lubricating agent if present, may be magnesium stearate, stearic acid or talc.
• the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/or dissolving tablets.
• Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
• Powders or granules for oral use may be provided in sachets or tubs.
• Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.
• Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.
• Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• the salt, hydrate, solvate or polymorphic form of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity.
• Suitable aqueous vehicles include Ringer’s solution and isotonic sodium chloride or glucose.
• Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
• suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth
• a wetting agent such as lecithin.
• Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
• the salt, hydrate, solvate, polymorphic form or pharmaceutical composition of the invention may also be presented as a liposome formulation.
• the salt, hydrate, solvate or polymorphic form of the invention will generally be provided in a form suitable for topical administration, e.g. as eye drops. Suitable forms may include ophthalmic solutions, gel-forming solutions, sterile powders for reconstitution, ophthalmic suspensions, ophthalmic ointments, ophthalmic emulsions, ophthalmic gels and ocular inserts. Alternatively, the salt, hydrate, solvate or polymorphic form of the invention may be provided in a form suitable for other types of ocular administration, for example as intraocular
• preparations including as irrigating solutions, as intraocular, intravitreal or juxtascleral injection formulations, or as intravitreal implants), as packs or corneal shields, as intracam eral, subconjunctival or retrobulbar injection formulations, or as iontophoresis formulations.
• the salt, hydrate, solvate, polymorphic form or pharmaceutical composition of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches.
• Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.
• the dose of the salt, hydrate, solvate or polymorphic form of the present invention will, of course, vary with the disease, disorder or condition to be treated or prevented.
• a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day.
• the desired dose may be presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day.
• the desired dose may be administered in unit dosage form, for example, containing l mg to 50 g of active ingredient per unit dosage form.
• any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention.
• any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.
• KF Thermogravimetric Analysis
• DSC Differential Scanning Calorimetry
• HPLC high performance liquid chromatography
• the software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA respectively. Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane. The details of the s data collection method used are:
• KF analysis was carried out on a Metrohm 874 Oven Sample Processor at 150 °C with 851 Titrano Coulometer using Hydranal Coulomat AG oven reagent and nitrogen purge. Weighed solid samples were introduced into a sealed sample vial. Approximately 10 mg of sample was used per titration and duplicate determinations were made. An average of these results is presented unless otherwise stated. Data collection and analysis were performed using Tiamo software.
• TGA data were collected on a TA Instruments Discovery TGA, equipped with a 25 position auto-sampler. Typically, 5-10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 25 ml/min was maintained over the sample.
• the instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.
• DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto- sampler. Typically, 0.5-3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 300 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample. Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every 60 seconds (period). The instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis or TRIOS.
• Reversed phase HPLC purity analysis was performed on an Agilent HP1100 series system equipped with a diode array detector and using ChemStation software.
• Example 2 jV-ffi.2. 3.f; .6. 7 -hexahvdro-s-indacen- 4 -yl)carbamoyl)-i-isopropyl-ilT- pyrazole-2-siilfonamide monosodium monohvdrate (Form 1) iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-ifT-pyrazole-3- sulfonamide free acid (50 mg) was treated with a 9:1 (v:v) solvent mixture of acetone and water (0.5 ml).
• the XRPD spectra shown in Figure 1 were obtained directly after preparation of the product, after storage for 1 week and for 5 weeks at 40°C and 75% relative humidity, and after storage for 1 week and for 5 weeks at 25°C and 97% relative humidity.
• the XRPD spectra shown in Figure 1 indicate that the product obtained in Example 2 shows stability with respect to conversion into other polymorphic forms after storage at elevated temperature and humidity.
• Example 2 A/-f(T.2.3.c;.6.7-hexahvdro-s-indacen- 4 -vDcarbamoylj-i-isopropyl-ijT- pyrazole-3-sulfonamide monosodium anhvdrate fForm 2) iV-((i,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-i-isopropyl-z/-/-pyrazole-3- sulfonamide monosodium salt (500 mg) was treated with a 10:1 (v:v) solvent mixture of isopropyl alcohol and H 2 0 (30 ml), and the reaction mixture was left stirring at 25 °C for 30 minutes. The resulting clear solution was then evaporated to produce a crystalline solid, which was analysed by XRPD, ⁇ -NMR, HPLC, IC, KF, TGA and DSC.
• the XRPD spectra shown in Figure 3 were obtained directly after preparation of the product, after storage for 1 week at 40°C and 75% relative humidity, and after storage for 1 week at 25°C and 97% relative humidity.
• Figure 3 also shows the XRPD spectrum for Form l polymorph for reference.
• the XRPD spectra shown in Figure 3 indicate that the monosodium anhydrate (Form 2) obtained in Example 3 is stable at elevated temperature (40°C), and converts to the monosodium monohydrate (Form 1) at elevated humidity (97% RH).
• Example 1 The sodium salt of Example 2 and the free acid of Comparative Example 1 were evaluated for solubility in water, stability in aqueous media and intrinsic dissolution rate. The results are set out in Table 5. Table 5
• thermodynamic aqueous solubility was measured in water.
• the sodium salt was found to be soluble in water (81 mg/ml) with a resulting pH of 9.7.
• the free acid was found to be very poorly soluble in water ( ⁇ 0.5 mg/ml).
• the sodium salt was dissolved in water at a concentration of 0.2 mg/ml. Due to the very poor aqueous solubility of the free acid, the free acid was dissolved in a 1:1 mixture of water and acetonitrile at the same
• the intrinsic dissolution rate was measured by the procedure set out in the US
• the sodium salts of Examples 1, 2 and 3 have improved properties as compared to the free acid and potassium salt of Comparative Examples 1 and 2. These improved properties include crystallinity, aqueous solubility, intrinsic dissolution rate, stability under storage at elevated temperature and/or relative humidity, and stability in aqueous media.

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